Research led by The University of Texas MD Anderson Cancer Center has identified a novel first-line treatment regimen that combines chemotherapy with targeted therapy to improve response rates for people with difficult to treat BRAF V600E-mutant metastatic colorectal cancer (mCRC).
The regimen involves concurrent chemotherapy with oxaliplatin, leucovorin, and 5-fluoruracil (collectively known as mFOLFOX6) plus the BRAF-inhibitor encorafenib and the EGFR-inhibitor cetuximab.
More than 150,000 people are diagnosed with colorectal cancer each year, making it the fourth most common cancer in the U.S., according to the National Cancer Institute. BRAF mutations occur in approximately 8–12% of cases and are associated with aggressive tumor growth.
“BRAF V600E is a poor prognosis subtype which has not responded well to traditional therapies with median progression free survival and response rates substantially lower than other CRC subtypes due to its distinct biology,” explained Scott Kopetz, MD, PhD, professor of gastrointestinal medical oncology and associate vice president of translational integration at The University of Texas MD Anderson Cancer Center.
He told Inside Precision Medicine that although BRAF targeted therapies have been approved for use in approved previously treated mCRC, up to now, they had not been studied as first-line therapy for these patients.
To address this, Kopetz and team carried out the phase III BREAKWATER study, which included 480 patients with stage IV metastatic disease and evidence of a BRAF V600E mutation. They were randomly assigned to receive encorafenib and cetuximab plus mFOLFOX6 (n=236) or standard-of-care (SOC) chemotherapy with or without bevacizumab (n=243).
As reported at the American Society of Clinical Oncology Gastrointestinal Cancers (ASCO GI) Annual Symposium and published in Nature Medicine, the objective response rate was significantly higher among the patients given encorafenib and cetuximab plus mFOLFOX6 than among those given SOC, at 60.9% versus 40.0%, with the difference between the two arms clinically relevant according to the researchers.
Furthermore, the triple combination showed similar benefits across all subgroups analyzed, including patients with cancer spread to three or more organs and those with liver metastases.
The median duration of response was 13.9 months in the encorafenib and cetuximab plus mFOLFOX6 arm versus 11.1 months in the SOC arm, while the proportions of patients with a response duration of at least six months were 68.7% and 34.1%, respectively.
During 10.3 months of follow-up, fewer patients died while receiving encorafenib and cetuximab plus mFOLFOX6 than did with SOC (16.9 vs 29.6%) but the difference between the two arms did not reach statistical significance at this first interim analysis. Follow-up is ongoing and data for progression-free survival will also be assessed in the next phase of the trial.
Kopetz said: “The high response rates and meaningful durability in the co-primary endpoint, and early trends towards higher survival in the interim analysis establishes this as a standard of care treatment for these patients in the first line. Collectively, the data suggests that upfront combination treatment is superior to a strategy of sequential treatment of chemotherapy followed by BRAF targeting.”
The safety profiles were consistent with those known for each agent. The most common adverse reactions included nausea, rash, fatigue, vomiting, abdominal pain, diarrhea and decreased appetite, all of which occurred in at least 25% of patients and were similar between arms.
The BREAKWATER trial was one of the first studies to utilize the FDA’s Project FrontRunner, an initiative to encourage the evaluation of therapies in earlier clinical settings for advanced cancers rather than after patients received numerous previous treatments. The data supported the accelerated approval of the encorafenib and cetuximab plus mFOLFOX6 combination by the Food and Drug Administration (FDA) in December 2024.
Kopetz said that the findings “highlight the importance of swiftly identifying molecular subtypes of colorectal cancer at diagnosis to optimize treatment strategies for our patients.”
He added: “If mutation test results are not available before treatment needs to be initiated, then it is reasonable to start with a backbone of FOLFOX alone for a cycle or two before making a decision about the appropriate targeted therapy to add.”
